Bone marrow derived stem cells are under intense study as potential therapeutic agents for a wide variety of pathologies. Treatment with exogenous bone marrow cells can improve myocardial function after infarct and brain function after stroke in rodents. Despite tremendous progress in the development of potential clinical uses of bone marrow stem cells, little is known about their normal in vivo functions or factors controlling their growth and differentiation. Further, nothing is known about the changes that occur in these cells once they move from the bone marrow to the blood, yet it is thought that the cells must travel through the blood to reach the site of tissue damage. Also, it has not been determined if circulating cells are equivalent to the multi-potent bone marrow stem cells, but preliminary data from our and other laboratories suggest that at a minimum, progenitors for many cell types reside in the blood. To begin to understand circulating stem cell biology we have focused on one type, namely circulating endothelial cell progenitors (CEPs), i.e, circulating cells that can differentiate into endothelial cells. Our first goal is to further the understanding of CEP biology by better delineating their phenotype(s) and identifying factors that control their growth and differentiation. This understanding may allow us to modulate CEP function in vivo to clinical advantage. Another component of stem cell biology about which little is known is how systemic disorders might alter their function. Our interest in particular is in how diabetes may affect CEP function. Evidence from our laboratory indicates that CEP dysfunction may be involved in diabetes associated vascular disease and that CEP therapy can improve vascularization in diabetic mice. Our second goal is to determine how the diabetic environment alters CEP function. To accomplish our goals we will 1) define the role of blood-derived CD34+ and CD14+ enriched cells in neovascularization in vivo; 2) identify molecular and cellular regulators of CEP growth and differentiation, and potential diabetes induced changes in these regulators in vivo; and 3) delineate potential roles of exogenous CEP modulators on CEP function in neovascularization in diabetic and non-diabetic mice.